1. Field of the Invention
The present invention relates to a method of delivery of medical devices to patients, especially a method where (e.g., neurological) devices are delivered using nonlinear magnetic stereotaxis in conjunction with non-invasive MR imaging observation techniques such as magnetic resonance imaging, and most especially where drug delivery by said devices is accomplished under real time, non-invasive observation techniques such as magnetic resonance imaging which can indicate metabolic responses to the delivered drug and/or changes in soluble/dispersed concentrations of materials within liquids and/or tissue of a patient in real time or near real time.
2. Background of the Prior Art
The concept of admninistering minimally invasive therapy and especially minimally invasive drug delivered therapy follows recent trends in medical and surgical practice towards increasing simplicity, safety, and therapeutic effectiveness. Image-guided, minimally invasive therapies have already superseded conventional surgical methods in several procedures. For example, transvascular coronary angioplasty is often now an alternative to open-heart surgery for coronary artery bypass, and laparascopic cholecystectomy is often an alternative to major abdominal surgery for gall bladder removal. The use of the less invasive techniques has typically reduced hospital stays by 1-2 weeks and the convalescence periods from 1-2 months to 1-2 weeks.
While endoscopic, arthroscopic, and endovascular therapies have already produced significant advances in health care, these techniques ultimately suffer from the same limitation. This limitation is that the accuracy of the procedure is "surface limited" by what the surgeon can either see through the device itself or otherwise visualize (as by optical fibers) during the course of the procedure. That is, the visually observable field of operation is quite small and limited to those surfaces (especially external surfaces of biological masses such as organs and other tissue) observable by visible radiation, due to the optical limitations of the viewing mechanism. MR imaging, by comparison, overcomes this limitation by enabling the physician or surgeon to non-invasively visualize tissue planes and structures (either in these planes or passing through them) beyond the surface of the tissue under direct evaluation. Moreover, MR imaging enables differentiation of normal from abnormal tissues, and it can display critical structures such as blood vessels in three dimensions. Prototype high-speed MR imagers which permit continuous real-time visualization of tissues during surgical and endovascular procedures have already been developed. MR-guided minimally invasive therapy is expected to substantially lower patient morbidity because of reduced post-procedure complications and pain. The use of this type of procedure will translate into shorter hospital stays, a reduced convalescence period before return to normal activities, and a generally higher quality of life for patients. The medical benefits and health care cost savings are likely to be very substantial.
A specific area where research is moving forward on advances of this type is in the treatment of neurological disorders. Specifically, the advent of new diagnostic and therapeutic technologies promises to extend the utility of intracerebral drug delivery procedures and thus possibly advance the efficacy of existing and/or planned treatments for various focal neurological disorders, neurovascular diseases and neurodegenerative processes. Currently, when the standard procedure requires neurosurgeons or interventional neuroradiologists to deliver drug therapy into the brain, the drug delivery device, such as a catheter, must either be passed directly through the intrapa-renchymal tissues to the targeted region of the brain, or guided through the vasculature until positioned properly. An important issue in either approach is the accuracy of the navigational process used to direct the movement of the drug delivery device. In many cases, the physical positioning of either part or all of the catheter's lumen within the brain is also important as, for example, in situations where a drug or some other therapeutic agent will be either inflsed or retroperfiised into the brain through the wall or from the tip of the catheter or other drug delivery device.
New technologies like intra-operative magnetic resonance imaging and nonlinear magnetic stereotaxis, the latter discussed by G. T. Gillies, R. C. Ritter, W. C. Broaddus, M. S. Grady, M. A. Howard III, and R. G. McNeil, "Magnetic Manipulation Instrumentation for Medical Physics Research," Review of Scientific Instruments, Vol.65, No.3, pp.533-562 (March 1994), as two examples, will likely play increasingly important roles here. In the former case, one type of MR unit is arranged in a "double-donut" configuration, in which the imaging coil is split axially into two components. Imaging studies of the patient are performed with this system while the surgeon is present in the axial gap and carrying out procedures on the patient. A second type of high-speed NMR imaging system combines high-resolution MR imaging with conventional X-ray fluoroscopy and digital subtraction angiography (DSA) capability in a single hybrid unit. These new generations of MR scanners are able to provide the clinician with frequently updated images of the anatomical structures of interest, therefore making it possible to tailor a given interventional procedure to sudden or acute changes in either the anatomical or physiological properties of, e.g., a part of the brain into which a drug agent is being infused.
Nonlinear magnetic stereotaxis is the image-based magnetically guided movement of a small object directly through the bulk brain tissues or along tracts within the neurovasculature or elsewhere within the body. Electromagnets are used to magnetically steer the implant, giving (for example) the neurosurgeon or interventional neuroradiologist the ability to guide the object along a particular path of interest. (The implant might be either magnetically and/or mechanically advanced towards its target, but is magnetically steered, in either case. That is, magnetic fields and gradients are used to provide torques and linear forces to orient or shift the position of the implant or device, with a mechanical pushing force subsequently providing none, some, or all of the force that actually propels the implant or device. Additional force may be provided magnetically.) The implant's position is monitored by bi-planar fluoroscopy, and its location is indicated on a computerized atlas of brain images derived from a preoperative MR scan. Among other applications, the implant might be used to tow a pliable catheter or other drug delivery device to a selected intracranial location through the brain parenchyma or via the neurovasculature. Magnetic manipulation of catheters and other probes is well documented in research literature. For example, Cares et al. (J. Neurosurg, 38:145, 1973) have described a magnetically guided microballoon released by RF induction heating, which was used to occlude experimental intracranial aneurysms. More recently, Kusunoki et al. (Neuroradiol 24: 127, 1982) described a magnetically controlled catheter with cranial balloon useful in treating experimental canine aneurysms. Ram and Meyer (Cathet. Cardiovas. Diag.22:317, 1991) have described a permanent magnet-tipped polyurethane angiography catheter useful in cardiac interventions, in particular intraventricular catheterization in neonates.
U.S. Pat. No. 4,869,247 teaches the general method of intra parenchymal and other types of magnetic manipulation, and U.S. Pat. Nos. 5,125,888; 5,707,335; and 5,779,694 describe the use of nonlinear magnetic stereotaxis to maneuver a drug or other therapy delivery catheter system within the brain. U.S. Pat. No. 5,654,864 teaches a general method of controlling the operation of the multiple coils of a magnetic stereotaxis system for the purpose of maneuvering an implant to precisely specified locations within the body.
Both of these technologies offer a capability for performing image-guided placement of a catheter or other drug delivery device, thus allowing drug delivery directly into the brain via infusion through the walls of the catheter or out flow of the tip off the catheter. In the case of drug delivery directly into the brain tissues, the screening of large molecular weight substances by the endothelial blood-brain barrier can be overcome. In the case of infusions into specific parts of the cerebrovasculature, highly selective catheterizations can be enabled by these techniques. In either case, however, detailed visual images denoting the actual position of the drug delivery device within the brain would be extremely useful to the clinician in maximizing the safety and efficacy of the procedure. The availability of an MR-visible drug delivery device combined with MR-visible drug agents would make it possible to obtain near real-time information on drug delivery during interventional procedures guided by non-linear magnetic stereotaxis. Drug delivery devices, such as catheters, that are both MR-visible and radio-opaque could be monitored by two modalities of imaging, thus making intra-operative verification of catheter location possible during nonlinear magnetic stereotaxis procedures. (Intra-operative MR assessment might require the temporary removal of the magnetic tip of the drug delivery catheter and interruption of the magnetic stereotaxis procedure to image the patient.).
The geometry and magnetic strength of the magnetic tip will depend upon the particular type of catheter or medical device with which the tip is being used. In a preferred embodiment, the tip would have as small a maximum dimension as would be consistent with maintaining sufficient magnetic dipole moment to couple satisfactorily to the external magnetic fields and gradients used to apply torques and forces to the tip for the purpose of steering or moving the catheter or other medical device. It is preferred that the magnetic element (e.g., a distinct magnetic bead or seed or wire) or the magnetic tip have a maximum dimension of at least 0.5 mm, preferably from 0.5 to 8 mm, more preferably from about 1.0 to 6 mm, and most preferably from about 2 to 5 or 6 mm. To that end, the tip might be made of a permanently magnetic or magnetically permeable material, with compounds of Nd--B--Fe being exemplary, as well as various iron alloys (ferrites and steel alloys). The magnetic tip may be fixed to the disttl end of the catheter in any number of ways, depending in part upon the method of use of the catheter, the specific type of catheter, the procedures and the use of the catheter. In one design, the magnetic tip might simply be a small spherical or oblate spheroid of magnetic material (e.g., having a geometry where the semi-major axis is from 1.1 to 3 times longer, preferably from 1.5 to 2.0 or 2.5 time longer than the semi-minor axis). The magnetic tip may be originally fixed to the distal end of the catheter or medical device or passed through the length of the catheter so that it abuts against the interal distal end of the catheter (as a foot would abut the end of a sock). As noted, the magnetic tip may be fixed in place either on the inside, outside or embedded within the composition of the distal end of the catheter or medical device. In a preferred embodiment, the magnetic tip may be thermally, solubly, mechanically, electronically or otherwise removably attached to and separable from the distal end of the catheter or medical device. A heat soluble link is taught in U.S. Pat. No. 5,125,888.
In still another embodiment, the magnetic tip would constitute a plug in the end of an otherwise open-ended catheter, and the tip might either have an open bore along its axis, a plurality of open bores along its axis, or a single or plural configuration of holes along the side of the magnetic tip, any of which openings would be used to facilitate drug delivery from the catheter or to serve as an exit port for the delivery of some other therapy or device into a body part, such as the parenchymal tissues and/or the cerebrobasculature of the brain. Alternatively, the magnetic tip might simply constitute a solid plug that seals the end of the catheter. The distal end of the catheter at which the magnetic tip is placed must be configured such that axial forces and torques applied by either magnetic fields and gradients or by a guide wire internal to the catheter allow said distal end and magnetic tip to be propelled towards a target site with the body, and to do so without said distal end and magnetic tip separating from each other in an inappropriate way and/or at an undesired time or under undesired circumstances. If the magnetic tip must be removed, or detached and removed, prior to MR imaging of the patient, such a procedure could be accomplished by the method taught in U.S. Pat. Nos. 5,125,888; 5,707,335; and 5,779,694, which call for dissolving a heat separable link between the tip and the catheter by a pulse of radio-frequency energy. An alternative means of removing the magnetic tip is discussed by M. A. Howard et al. in their article, "Magnetically Guided Stereotaxis," in Advanced Neurosurgical Navigation, edited by E. Alexander III and R. J. Maciunas (Thieme Medical Publisher, New York, 1998), which calls for withdrawing the magnetic tip from along the inside of the catheter that it has just steered into place within the body. Without removal of the magnetic tip from the catheter, whole body magnetic forces might be produced on it by the field of the MR imaging system, and these could cause undesired movement of the catheter that it has just steered into place within the body.
In the treatment of neurological diseases and disorders, targeted drug delivery can significantly improve therapeutic efficacy, while minimizing systemic side-effects of the drug therapy. Image-guided placement of the tip of a drug delivery catheter directly into specific regions of the brain can initially produce maximal drug concentration-close to some targeted loci of tissue receptors following delivery of the drug. At the same time, the limited distribution of drug injected from a single catheter tip presents other problems. For example, the volume flow rate of drug delivery must be very low to avoid indiscriminate hydrodynamic damage or other damage to brain cells and nerve fibers. Delivery of a drug from a single point source may also limit the distribution of the drug by decreasing the effective radius of penetration of the drug agent into the surrounding tissue receptor population. Positive pressure infusion, i.e., convection-enhanced delivery of drugs into the brain, as taught by U.S. Pat. No. 5,720,720 may overcome the problem of effective radius of penetration. Also, U.S. patent application Ser. No. 08/857,043, filed on May 15, 1997 and titled "Method and Apparatus for Use with MR Imaging" describes a technology invented in-part by one of the present inventors comprising a method for observing the delivery of material to tissue in a living patient comprising the steps of a) observing by magnetic resonance imaging a visible image within an area or volume comprising tissue of said living patient, the area or volume including a material delivery device, b) delivering at least some material by the material delivery device into the area or volume comprising tissue of a living patient, and c) observing a change in property of said visible image of the area or volume comprising tissue of a living patient while said material delivery device is still present within the area or volume. This process, including the MRI visualization, is performed in approximately or actually real time, with the clinical procedure being guided by the MRI visualization.
Research on magnetic catheterization of cerebral blood vessels generally has focused on design of transvascular devices to thrombose aneurysms, to deliver cytotaxic drugs to tumors, and to deliver other therapies without the risks of major invasive surgery. Examples of such studies include Hilal et al (J.Appl. Phys. 40:1046, 1969), Molcho et al (IEEE Trans. Biomed. Eng. BME-17, 134, 1970), Penn et al (J. Neurosurg. 38:239, 1973), and Hilal et al (Radiology 113:529,1974).
U.S. Pat. Nos. 4,869,247, 5,654,864, 5,125,888, 5,707,335 and 5,779,694 describe processes and apparatus for the use of magnetic stereotaxis for the manipulation of an object or implant which is moved into position within a patient, particularly within the cranial region and specifically within the brain but in principle elsewhere in the body also. These patents do no not involve any contemplation of real time visualization of drug distribution within the brain, especially by MRI. It should be noted that the potential exists for interactive interference between the two systems, magnetic resonance imaging and magnetic stereotaxis, particularly where fine images are being provided by a system based on magnetic coils, especially as described in U.S. patent application Ser. No. 08/916,596, filed on Aug. 22, 1997, which is incorporated herein by reference for its disclosure of the design, construction, structure and operation of coils and catheters in MR-guided procedures.
A source of drug delivery can be effected by devising a multi-lumen catheter with multiple drug release sources that effectively disperse therapeutic drug agents over a brain region containing receptors for the drug, or over an anatomically extensive area of brain pathology. A preferred type of structure is described in U.S. patent application Ser. No. 08/916,596, filed on Aug. 22, 1997, but other devices which are described in the background of the art in that application could also be used in the practice of the present invention.
It should be noted that the potential exists for interactive interference between the two systems, i.e., magnetic resonance imaging and magnetic stereotaxis. This is because both modalities rely on the creation of large external magnetic fields to function as designed. The magnetic field and field gradients of the magnetic stereotaxis system are used to steer an implant within the body, and especially within the brain, while the magnetic fields of the magnetic resonance imager are used to create images of the planes of tissue within the patient's body. The magnetic fields of either one of these systems/devices can perturb the size and shape (and, therefore, the function) of the fields of the other device. It is unlikely that a clinical configuration of these systems/devices would be purposely arranged so as to cause direct interference via interaction of the fields. However, a far more likely danger is that the magnetic tip of the implanted catheter or other MSS-guided device will experience bulk-body forces and torques if the patient is placed in the MR and is subjected to the resulting magnetic field produced during the course of its functioning. Such a field could very easily cause the magnetically-tipped implant to move away from the location into which it was navigated by the clinician operating the magnetic sterotaxis system. This might produce a dangerous situation for the patient and, hence, care must be taken to insure that the magnetic tip is either removed from the catheter in the patient prior to MR imaging, or that it is otherwise deactivated or made impervious to the effects of non-MSS fields to which it might be subjected. Moreover, the presence of a relatively large magnetic dipole in the patient's body, as might arise from the presence of the magnetic tip of the implanted catheter, would create artifacts in the MR images.